Generation and characterization of HLA-A2 transgenic mice expressing the human TCR 1G4 specific for the HLA-A2 restricted NY-ESO-1(157-165) tumor-specific peptide.

NY-ESO-1 is a tumor-specific, highly immunogenic, human germ cell antigen of the MAGE-1 family that is a promising vaccine and cell therapy candidate in clinical trial development. The mouse genome does not encode an NY-ESO-1 homolog thereby not subjecting transgenic T-cells to thymic tolerance mechanisms that might impair in-vivo studies. We hypothesized that an NY-ESO-1 T cell receptor (TCR) transgenic mouse would provide the unique opportunity to study avidity of TCR response against NY-ESO-1 for tumor vaccine and cellular therapy development against this clinically relevant and physiological human antigen. To study in vitro and in vivo the requirements for shaping an effective T cell response against the clinically relevant NY-ESO-1, we generated a C57BL/6 HLA-A*0201 background TCR transgenic mouse encoding the 1G4 TCR specific for the human HLA-A2 restricted, NY-ESO-1157-165 SLLMWITQC (9C), initially identified in an NY-ESO-1 positive melanoma patient. The HLA-A*0201 restricted TCR was positively selected on both CD4+ and CD8+ cells. Mouse 1G4 T cells were not activated by endogenous autoimmune targets or a large library of non-cognate viral antigens. In contrast, their activation by HLA-A2 NY-ESO-1157-165 complexes was evident by proliferation, CD69 upregulation, interferon-γ production, and interleukin-2 production, and could be tuned using a twofold higher affinity altered peptide ligand, NY-ESO-1157-165V. NY-ESO-1157-165V recombinant vaccination of syngeneic mice adoptively transferred with m1G4 CD8+ T cells controlled tumor growth in vivo. 1G4 transgenic mice suppressed growth of syngeneic methylcholanthrene (MCA) induced HHD tumor cells expressing the full-length human NY-ESO-1 protein but not MCA HHD tumor cells lacking NY-ESO-1. The 1G4 TCR mouse model for the physiological human TCR against the clinically relevant antigen, NY-ESO-1, is a valuable tool with the potential to accelerate clinical development of NY-ESO-1-targeted T-cell and vaccine therapies.

Shenderov E ，Kandasamy M ，Gileadi U ，Chen J ，Shepherd D ，Gibbs J ，Prota G ，Silk JD ，Yewdell JW ，Cerundolo V ... -  《Journal for ImmunoTherapy of Cancer》

Identification of NY-ESO-1(157-165) Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy.

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target for T-cell receptor-engineered T cell (TCR-T) therapy, and targeting the human leukocyte antigen (HLA)-A2 restricted NY-ESO-1157-165 epitope has yielded remarkable clinical benefits in the treatment of multiple advanced malignancies. Herein, we report the identification of two NY-ESO-1157-165 epitope-specific murine TCRs obtained from HLA-A*0201 transgenic mice. NY-ESO-1157-165 specific TCRs were isolated after vaccinating HLA-A2 transgenic mice with epitope peptides. HZ6 and HZ8 TCRs could specifically bind to NY-ESO-1157-165/HLA-A2 and were capable of cytokine secretion with engineered Jurkat T cells and primary T cells upon recognition with K562 target cells expressing the single-chain trimer (SCT) of NY-ESO-1157-165/HLA-A2. The reactivity profiles of the HZ6 and HZ8 TCRs were found to be distinct from one another when co-cultured with K562 target cells carrying alanine-substituted NY-ESO-1157-165 SCTs. The binding characterization revealed that the recognition pattern of the HZ6 TCR to NY-ESO-1157-165/HLA-A2 was substantially different from the widely used 1G4 TCR. These findings would broaden the understanding of immunogenicity of the NY-ESO-1157-165, and the two identified TCRs may serve as promising candidates for the future development of TCR-T therapy for tumors.

Zhang H ，Sun M ，Wang J ，Zeng B ，Cao X ，Han Y ，Tan S ，Gao GF ... -  《Frontiers in Immunology》

Chronic TCR-MHC (self)-interactions limit the functional potential of TCR affinity-increased CD8 T lymphocytes.

Duong MN ，Erdes E ，Hebeisen M ，Rufer N ... -  《Journal for ImmunoTherapy of Cancer》

A rare population of tumor antigen-specific CD4(+)CD8(+) double-positive αβ T lymphocytes uniquely provide CD8-independent TCR genes for engineering therapeutic T cells.

Matsuzaki J ，Tsuji T ，Chodon T ，Ryan C ，Koya RC ，Odunsi K ... -  《Journal for ImmunoTherapy of Cancer》

NY-ESO-1 protein formulated in ISCOMATRIX adjuvant is a potent anticancer vaccine inducing both humoral and CD8+ t-cell-mediated immunity and protection against NY-ESO-1+ tumors.

Maraskovsky E ，Sjölander S ，Drane DP ，Schnurr M ，Le TT ，Mateo L ，Luft T ，Masterman KA ，Tai TY ，Chen Q ，Green S ，Sjölander A ，Pearse MJ ，Lemonnier FA ，Chen W ，Cebon J ，Suhrbier A ... -  《CLINICAL CANCER RESEARCH》